CN114702498B - Acid addition salts of dihydropyrimidine derivatives and their use in medicine - Google Patents

Acid addition salts of dihydropyrimidine derivatives and their use in medicine Download PDF

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CN114702498B
CN114702498B CN202210330417.9A CN202210330417A CN114702498B CN 114702498 B CN114702498 B CN 114702498B CN 202210330417 A CN202210330417 A CN 202210330417A CN 114702498 B CN114702498 B CN 114702498B
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张珉
刘辛昌
时佳佳
尹丽华
闫兴国
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Abstract

The invention discloses an acid addition salt of a dihydropyrimidine derivative and application thereof in medicines. The invention particularly relates to a hydrochloride crystal form A, a hydrochloride crystal form B, a sulfate crystal form A, a hydrobromide crystal form A, a phosphate crystal form A, a mesylate crystal form A or a mesylate crystal form B of a compound shown as a formula (I) or a formula (Ia) and application thereof in medicines. The salts of the invention have good stability under high temperature, high humidity and light conditions, and have good pharmacokinetic properties in beagle dogs.
Figure DDA0003575083890000011

Description

Acid addition salts of dihydropyrimidine derivatives and their use in medicine
Technical Field
The invention belongs to the technical field of chemical medicines, and particularly relates to an acid addition salt of a dihydropyrimidine derivative and application thereof in medicines.
Background
Hepatitis b virus belongs to the hepadnaviridae family. It can cause acute and/or persistent progressive chronic disease. Hepatitis b virus also causes many other clinical manifestations in pathological morphology-in particular chronic inflammation of the liver, cirrhosis and canceration of hepatocytes. In addition, co-infection with hepatitis delta can have adverse effects on the progression of the disease.
The conventional drugs licensed for the treatment of chronic hepatitis are interferon and lamivudine (lamivudine). However, interferons have only moderate activity and high toxic side effects; lamivudine (lamivudine) has good activity, but its resistance increases rapidly during treatment and often shows rebound effects after treatment is stopped.
In the related art, heteroaromatic ring substituted dihydropyrimidine (HAP) compounds represented by Bay41-4109 and Bay39-5493 can inhibit HBV replication by preventing normal nucleocapsid formation, however, the study on the action mechanism thereof has found that heteroaromatic ring substituted dihydropyrimidine compounds change the angle between nucleocapsid forming dimers by acting on 113-143 amino acid residues of core protein, resulting in unstable swollen nucleocapsid formation, which accelerates degradation of core protein.
In addition, WO2015132276 discloses a number of dihydropyrimidines having a better inhibitory effect on HBV viral replication, of which example 25, (4- ((S) -7- (((R) -6- (2-chloro-4-fluorophenyl) -5- (methoxycarbonyl) -2- (thiazol-2-yl) -3,6-dihydropyrimidin-4-yl) methyl) -3-oxohexahydroimidazo [1,5-a ] pyrazin-2 (3H) -yl) benzoic acid (I) has a better activity.
Figure RE-GDA0003680091810000011
However, the inventors found that in the process of preparing the compound (4- ((S) -7- (((R) -6- (2-chloro-4-fluorophenyl) -5- (methoxycarbonyl) -2- (thiazol-2-yl) -3,6-dihydropyrimidin-4-yl) methyl) -3-oxohexahydroimidazo [1,5-a ] pyrazin-2 (3H) -yl) benzoic acid (I) and its tautomer (4- ((S) -7- (((R) -6- (2-chloro-4-fluorophenyl) -5- (methoxycarbonyl) -2- (thiazol-2-yl) -1,6-dihydropyrimidin-4-yl) methyl) -3-oxohexahydroimidazo [1,5-a ] pyrazin-2 (3H) -yl) benzoic acid (Ia), the stability and the pharmacokinetic properties of the compound were not satisfactory, and a lot of inconvenience was brought to the development of the formulation at a later stage.
As is well known, different crystal forms, salt forms or salt forms of the same drug may have obvious differences in the aspects of stability, solubility, bioavailability and the like, so that the curative effect of the drug is affected, and therefore, the development of the crystal form of the salt of the dihydropyrimidine derivative, which is more favorable for better stability and pharmacokinetic data, has important significance.
Disclosure of Invention
The present invention is directed to solving at least one of the above problems in the prior art. To this end, the present invention provides an acid addition salt of a dihydropyrimidine derivative.
The invention also provides a pharmaceutical composition.
The invention also provides the use of an acid addition salt of a dihydropyrimidine derivative in medicine.
The invention provides an acid addition salt of a compound shown as a formula (I) or a formula (Ia), wherein the acid addition salt comprises a hydrochloride crystal form A, a hydrochloride crystal form B, a sulfate crystal form A, a hydrobromide crystal form A, a phosphate crystal form A, a mesylate crystal form A or a mesylate crystal form B;
Figure RE-GDA0003680091810000021
wherein the X-ray powder diffraction pattern of the hydrochloride form A comprises diffraction peaks with 2 theta angles of 11.99 +/-0.2 degrees, 12.84 +/-0.2 degrees, 13.18 +/-0.2 degrees, 16.26 +/-0.2 degrees, 17.60 +/-0.2 degrees and 18.35 +/-0.2 degrees;
the X-ray powder diffraction pattern of the hydrochloride crystal form B comprises diffraction peaks with 2 theta angles of 11.95 +/-0.2 degrees, 13.05 +/-0.2 degrees, 13.53 +/-0.2 degrees, 14.50 +/-0.2 degrees, 18.21 +/-0.2 degrees and 18.93 +/-0.2 degrees;
the X-ray powder diffraction pattern of the mesylate crystal form A comprises diffraction peaks with 2 theta angles of 10.21 +/-0.2 degrees, 13.38 +/-0.2 degrees, 14.86 +/-0.2 degrees, 15.80 +/-0.2 degrees, 18.38 +/-0.2 degrees and 21.06 +/-0.2 degrees;
the X-ray powder diffraction pattern of the mesylate crystal form B comprises diffraction peaks with 2 theta angles of 6.69 +/-0.2 degrees, 12.15 +/-0.2 degrees, 15.10 +/-0.2 degrees, 18.41 +/-0.2 degrees, 22.44 +/-0.2 degrees and 24.54 +/-0.2 degrees;
the X-ray powder diffraction pattern of the sulfate crystal form A comprises diffraction peaks with 2 theta angles of 5.94 +/-0.2 degrees, 11.34 +/-0.2 degrees, 12.73 +/-0.2 degrees, 15.15 +/-0.2 degrees, 16.82 +/-0.2 degrees and 19.23 +/-0.2 degrees;
the X-ray powder diffraction pattern of the hydrobromide crystal form A comprises diffraction peaks with 2 theta angles of 6.00 +/-0.2 degrees, 9.56 +/-0.2 degrees, 12.06 +/-0.2 degrees, 13.04 +/-0.2 degrees, 16.26 +/-0.2 degrees and 18.30 +/-0.2 degrees;
the X-ray powder diffraction pattern of the phosphate crystal form A comprises diffraction peaks with 2 theta angles of 5.81 +/-0.2 degrees, 11.85 +/-0.2 degrees, 12.85 +/-0.2 degrees, 15.53 +/-0.2 degrees, 17.35 +/-0.2 degrees and 18.22 +/-0.2 degrees.
The acid addition salts described in connection with the present invention have at least the following beneficial effects:
the crystal form of the acid addition salt has high stability under the conditions of high temperature, high humidity and illumination, and has better pharmacokinetic property in beagle dogs.
According to some embodiments of the invention, the X-ray powder diffraction pattern of form a of the hydrochloride salt of the present invention comprises diffraction peaks at 2 Θ angles of 10.07 ± 0.2 °, 11.34 ± 0.2 °, 11.99 ± 0.2 °, 12.84 ± 0.2 °, 13.18 ± 0.2 °, 16.26 ± 0.2 °, 17.60 ± 0.2 °, 18.35 ± 0.2 °, 19.18 ± 0.2 °, 20.09 ± 0.2 ° and 20.77 ± 0.2 °.
According to some embodiments of the invention, the X-ray powder diffraction pattern of form B of the hydrochloride salt of the invention comprises diffraction peaks at 2 Θ angles of 11.95 ± 0.2 °, 13.05 ± 0.2 °, 13.53 ± 0.2 °, 14.50 ± 0.2 °, 16.61 ± 0.2 °, 18.21 ± 0.2 °, 18.93 ± 0.2 °, 19.92 ± 0.2 °, 22.37 ± 0.2 ° and 23.14 ± 0.2 °.
According to some embodiments of the invention, the form a of the sulfate salt of the present invention has an X-ray powder diffraction pattern comprising diffraction peaks at 2 Θ angles of 5.94 ± 0.2 °, 11.34 ± 0.2 °, 12.73 ± 0.2 °, 14.14 ± 0.2 °, 15.15 ± 0.2 °, 16.82 ± 0.2 °, 17.43 ± 0.2 °, 18.53 ± 0.2 °, 19.23 ± 0.2 °, and 22.02 ± 0.2 °.
According to some embodiments of the invention, the X-ray powder diffraction pattern of the hydrobromide form a of the invention comprises diffraction peaks with 2 θ angles of 6.00 ± 0.2 °, 6.80 ± 0.2 °, 9.56 ± 0.2 °, 12.06 ± 0.2 °, 13.04 ± 0.2 °, 16.26 ± 0.2 °, 18.30 ± 0.2 °, 19.15 ± 0.2 °, 19.98 ± 0.2 ° and 22.61 ± 0.2 °.
According to some embodiments of the invention, the X-ray powder diffraction pattern of phosphate form a of the present invention comprises diffraction peaks at 2 Θ angles of 5.81 ± 0.2 °, 6.46 ± 0.2 °, 11.85 ± 0.2 °, 12.85 ± 0.2 °, 15.53 ± 0.2 °, 17.35 ± 0.2 °, 18.22 ± 0.2 °, 19.32 ± 0.2 °, 20.79 ± 0.2 °, 23.20 ± 0.2 °, and 23.79 ± 0.2 °.
According to some embodiments of the invention, the X-ray powder diffraction pattern of mesylate salt form a of the invention comprises diffraction peaks at 2 Θ angles of 7.91 ± 0.2 °, 9.69 ± 0.2 °, 10.21 ± 0.2 °, 11.51 ± 0.2 °, 13.38 ± 0.2 °, 14.86 ± 0.2 °, 15.80 ± 0.2 °, 16.82 ± 0.2 °, 18.38 ± 0.2 °, 19.16 ± 0.2 °, and 21.06 ± 0.2 °.
According to some embodiments of the invention, the X-ray powder diffraction pattern of crystalline form B of the mesylate salt of the invention comprises diffraction peaks at 2 Θ angles of 6.69 ± 0.2 °, 12.15 ± 0.2 °, 12.98 ± 0.2 °, 14.34 ± 0.2 °, 15.10 ± 0.2 °, 16.50 ± 0.2 °, 18.41 ± 0.2 °, 22.44 ± 0.2 °, 22.94 ± 0.2 ° and 24.54 ± 0.2 °.
According to some embodiments of the present invention, the, the X-ray powder diffraction pattern of the hydrochloride crystal form A comprises 2 theta angles of 8.78 +/-0.2 degrees, 9.55 +/-0.2 degrees, 10.07 +/-0.2 degrees, 11.34 +/-0.2 degrees, 11.99 +/-0.2 degrees, 12.43 +/-0.2 degrees, 12.84 +/-0.2 degrees, 13.18 +/-0.2 degrees, 13.59 +/-0.2 degrees, 15.07 +/-0.2 degrees, 15.40 +/-0.2 degrees, 16.26 +/-0.2 degrees, 17.04 +/-0.2 degrees, 17.60 +/-0.2 degrees, 17.96 +/-0.2 degrees, 18.35 +/-0.2 degrees, 19.18 +/-0.2 degrees diffraction peaks of 19.32 + -0.2 °, 20.09 + -0.2 °, 20.77 + -0.2 °, 21.77 + -0.2 °, 22.05 + -0.2 °, 22.77 + -0.2 °, 23.53 + -0.2 °, 23.78 + -0.2 °, 24.34 + -0.2 °, 24.99 + -0.2 °, 25.46 + -0.2 °, 25.65 + -0.2 °, 25.87 + -0.2 °, 26.13 + -0.2 °, 26.56 + -0.2 °, 26.98 + -0.2 °, 28.62 + -0.2 °, 29.10 + -0.2 ° and 30.44 + -0.2 °.
According to some embodiments of the invention, the X-ray powder diffraction pattern of the hydrochloride form B of the invention comprises diffraction peaks at 2 θ of 8.72 ± 0.2 °, 11.95 ± 0.2 °, 12.71 ± 0.2 °, 13.05 ± 0.2 °, 13.53 ± 0.2 °, 14.50 ± 0.2 °, 16.61 ± 0.2 °, 17.21 ± 0.2 °, 17.48 ± 0.2 °, 17.81 ± 0.2 °, 18.21 ± 0.2 °, 18.93 ± 0.2 °, 19.34 ± 0.2 °, 19.92 ± 0.2 °, 22.37 ± 0.2 °, 22.57 ± 0.2 °, 23.14 ± 0.2 °, 23.48 ± 0.2 °, 23.86 ± 0.2 °, 24.16 ± 0.2 °, 24.35 ± 0.2 °, 24.74 ± 0.2 °, 24.90 ± 0.25.25 ± 0.26.26 ± 0.26 °, 3228 ± 0.28 °.
According to some embodiments of the invention, the X-ray powder diffraction pattern of the sulfate form a of the invention comprises diffraction peaks at ± 370.27 °, 370.2 °, 370.19 °, 12.0 ± 0.2 °, 13.66 ± 0.2 °, 14.14 ± 0.2 °, 15.15 ± 0.2 °, 16.19 ± 0.2 °, 16.82 ± 0.2 °, 17.43 ± 0.2 °, 17.70 ± 0.2 °, 18.53 ± 0.2 °, 19.23 ± 0.2 °, 19.64 ± 0.2 °, 20.63 ± 0.2 °, 20.92 ± 0.2 °, 21.63 ± 0.2 °, 22.02 ± 0.2 °, 22.24 ± 0.2 °, 22.84 ± 0.2 °, 23.80 ± 0.2 °, 23.97 ± 0.2 °, 24.70 ± 0.2 °, 21.25.25 ± 0.2 °, 22.02 ± 0.2 °, 22.24 ± 0.2 °, 370.27 ± 0.27 °, 370.27 ± 0.2 °, 370.63 ± 0.2 °, 370.2 °, 370.85 °, 370.28 °, 370 ° z ± 0.2 °.
According to some embodiments of the present invention, the, the X-ray powder diffraction pattern of the hydrobromide crystal form A comprises 2 theta angles of 6.00 +/-0.2 degrees, 6.80 +/-0.2 degrees, 8.74 +/-0.2 degrees, 9.56 +/-0.2 degrees, 9.96 +/-0.2 degrees, 12.06 +/-0.2 degrees, 13.04 +/-0.2 degrees, 15.12 +/-0.2 degrees, 15.37 +/-0.2 degrees, 16.26 +/-0.2 degrees, 17.55 +/-0.2 degrees, 18.03 +/-0.2 degrees, 18.30 +/-0.2 degrees, 19.15 +/-0.2 degrees, 19.36 +/-0.2 degrees, 19.98 +/-0.2 degrees diffraction peaks of 20.13 + -0.2 deg., 20.64 + -0.2 deg., 21.33 + -0.2 deg., 21.91 + -0.2 deg., 22.44 + -0.2 deg., 22.61 + -0.2 deg., 23.71 + -0.2 deg., 24.19 + -0.2 deg., 24.99 + -0.2 deg., 25.21 + -0.2 deg., 25.44 + -0.2 deg., 26.19 + -0.2 deg., 26.44 + -0.2 deg., 26.85 + -0.2 deg., 27.05 + -0.2 deg., 27.66 + -0.2 deg., 28.97 + -0.2 deg., and 30.47 + -0.2 deg..
According to some embodiments of the invention, the X-ray powder diffraction pattern of phosphate form a of the present invention comprises diffraction peaks at 2 Θ angles of 5.81 ± 0.2 °, 6.46 ± 0.2 °, 11.85 ± 0.2 °, 12.85 ± 0.2 °, 14.10 ± 0.2 °, 15.53 ± 0.2 °, 16.90 ± 0.2 °, 17.35 ± 0.2 °, 18.22 ± 0.2 °, 19.32 ± 0.2 °, 20.79 ± 0.2 °, 23.20 ± 0.2 °, 23.79 ± 0.2 °, 24.80 ± 0.2 °, 25.64 ± 0.2 °, 27.33 ± 0.2 °, 28.26 ± 0.2 °, 28.97 ± 0.2 °, 29.62 ± 0.2 °, and 30.38 ± 0.2 °.
According to some embodiments of the present invention, the, the X-ray powder diffraction pattern of the mesylate crystal form A comprises 3.98 +/-0.2 degrees, 7.91 +/-0.2 degrees, 9.69 +/-0.2 degrees, 10.21 +/-0.2 degrees, 11.51 +/-0.2 degrees, 11.86 +/-0.2 degrees, 12.11 +/-0.2 degrees, 13.38 +/-0.2 degrees, 14.86 +/-0.2 degrees, 15.21 +/-0.2 degrees, 15.80 +/-0.2 degrees, 16.82 +/-0.2 degrees, 18.12 +/-0.2 degrees, 18.38 +/-0.2 degrees, 19.16 +/-0.2 degrees, 19.62 +/-0.2 degrees, 21.06 +/-0.2 degrees, 21.66 +/-0.2 degrees, 22.06 +/-0.2 degrees, 22.57 +/-0.2 degrees, 23.35 +/-0.2 degrees, 23.81 +/-0.2 degrees, 24.20 +/-0.2 degrees diffraction peaks at 24.90 + -0.2 °, 25.17 + -0.2 °, 26.35 + -0.2 °, 26.92 + -0.2 °, 28.42 + -0.2 °, 29.03 + -0.2 °, 29.89 + -0.2 °, 30.89 + -0.2 °, 31.52 + -0.2 °, 31.90 + -0.2 °, 32.92 + -0.2 °, 34.94 + -0.2 °, 35.78 + -0.2 °, 3926 + -0.2 °, 38.57 + -0.2 °, 39.59 + -0.2 °, 40.20 + -0.2 °, 40.82 + -0.2 °, 41.67 + -0.2 °, 42.35 + -0.2 °, 43.75 + -0.2 °, 44.98 + -0.2 °, 46.66 + -0.2 ° and 3549.02 + -0.2 °.
According to some embodiments of the present invention, the X-ray powder diffraction pattern of mesylate form B of the present invention comprises ± 0.2 ° diffraction peaks at ± 0.2 ° 2.53 ± 0.2 °, 6.69 ± 0.2 °, 12.15 ± 0.2 °, 12.46 ± 0.2 °, 12.98 ± 0.2 °, 14.34 ± 0.2 °, 15.10 ± 0.2 °, 16.35 ± 0.2 °, 16.50 ± 0.2 °, 17.59 ± 0.2 °, 17.80 ± 0.2 °, 18.41 ± 0.2 °, 19.05 ± 0.2 °, 19.43 ± 0.2 °, 19.68 ± 0.2 °, 20.04 ± 0.2 °, 20.52 ± 0.2 °, 20.79 ± 0.2 °, 21.72 ± 0.2 °, 8978 ± 0.2 °, 22.44 ± 0.2 °, 22.83 ± 0.2 °, 22.94 ± 0.22.74 ± 0.2 °, 23.24 ± 0.24 ± 0.28 °, 22.28 ± 0.28 ± 0.27 ± 0.28 °,22 ± 0.28 ± 0.26 °,2 °.
According to some embodiments of the invention, the hydrochloride form a of the present invention has an X-ray powder diffraction pattern substantially as shown in figure 1.
According to some embodiments of the invention, the hydrochloride form B of the present invention has an X-ray powder diffraction pattern substantially as shown in figure 3.
According to some embodiments of the invention, the crystalline form a of the sulfate salt of the present invention has an X-ray powder diffraction pattern substantially as shown in figure 5.
According to some embodiments of the invention, the crystalline form a of the hydrobromide salt of the invention has an X-ray powder diffraction pattern substantially as shown in figure 7.
According to some embodiments of the invention, the phosphate form a of the present invention has an X-ray powder diffraction pattern substantially as shown in figure 9.
According to some embodiments of the invention, the mesylate salt form a of the invention has an X-ray powder diffraction pattern substantially as shown in figure 11.
According to some embodiments of the invention, the mesylate salt form B of the invention has an X-ray powder diffraction pattern substantially as shown in figure 13.
According to some embodiments of the invention, the differential scanning calorimetry trace of form a of the hydrochloride salt of the invention comprises an endothermic peak at 211.0 ℃ ± 3 ℃.
According to some embodiments of the invention, the differential scanning calorimetry plot of form B of the hydrochloride salt of the invention comprises endothermic peaks at 183.2 ℃ ± 3 ℃ and 214.0 ℃ ± 3 ℃.
According to some embodiments of the invention, the differential scanning calorimetry trace of form a of the sulfate salt of the invention comprises endothermic peaks at 156.0 ℃ ± 3 ℃ and 213.3 ℃ ± 3 ℃.
According to some embodiments of the invention, the differential scanning calorimetry trace of the crystalline form a of the hydrobromide of the invention comprises an endothermic peak at 228.2 ℃ ± 3 ℃.
According to some embodiments of the invention, the differential scanning calorimetry trace of form a of the phosphate salt of the invention comprises an endothermic peak at 207.2 ℃ ± 3 ℃.
According to some embodiments of the invention, the differential scanning calorimetry trace of said mesylate salt form a of the invention comprises an endothermic peak at 217.0 ℃ ± 3 ℃.
According to some embodiments of the invention, the differential scanning calorimetry trace of said mesylate salt form B of the invention comprises an endothermic peak at 197.0 ℃ ± 3 ℃.
According to some embodiments of the invention, the hydrochloride salt form a of the present invention has a differential scanning calorimetry pattern substantially as shown in figure 2.
According to some embodiments of the invention, the hydrochloride salt form B of the present invention has a differential scanning calorimetry trace substantially as shown in figure 4.
According to some embodiments of the invention, the crystalline form a of the sulfate salt of the present invention has a differential scanning calorimetry pattern substantially as shown in figure 6.
According to some embodiments of the present invention, the hydrobromide form a of the present invention has a differential scanning calorimetry pattern substantially as shown in figure 8.
According to some embodiments of the invention, the phosphate form a of the present invention has a differential scanning calorimetry trace substantially as shown in figure 10.
According to some embodiments of the invention, the mesylate salt form a of the invention has a differential scanning calorimetry pattern substantially as shown in figure 12.
According to some embodiments of the invention, the mesylate salt form B of the invention has a differential scanning calorimetry pattern substantially as shown in figure 14.
In a second aspect, the present invention provides a pharmaceutical composition comprising the acid addition salt of the present invention and a pharmaceutically acceptable excipient.
According to some embodiments of the invention, the excipient is a carrier, excipient or diluent.
In a third aspect, the invention provides the use of an acid addition salt according to the invention or a pharmaceutical composition comprising said acid addition salt for the manufacture of a medicament, particularly for the prevention, treatment or alleviation of a viral disease in a patient.
According to some embodiments of the invention, the viral disease is hepatitis b infection or a disease caused by hepatitis b infection.
According to some embodiments of the invention, the disease caused by hepatitis b infection is cirrhosis or hepatocellular carcinoma.
Detailed description of the invention
The invention is intended to cover alternatives, modifications and equivalents, which may be included within the scope of the invention as defined by the appended claims. Those skilled in the art will recognize that many methods and materials similar or equivalent to those described herein can be used in the practice of the present invention. The present invention is in no way limited to the methods and materials described herein. In the event that one or more of the incorporated documents, patents, and similar materials differ or contradict this application (including but not limited to defined terminology, application of terminology, described techniques, and the like), this application controls.
In the present invention, the crystalline form of the acid addition salt of the compound represented by formula (I) or formula (Ia) may contain a solvent, and in some cases, the solvent may contribute to the internal stability of the crystalline form of the acid addition salt of compound (I), compound (Ia), and common solvents include water, ethanol, methanol, isopropanol, acetone, isopropyl ether, diethyl ether, isopropyl acetate, n-heptane, tetrahydrofuran, dichloromethane, ethyl acetate, and the like. The above-mentioned crystal forms with a certain amount of moisture or other solvents should be considered to be included in the scope of the present invention as long as they have any of the characteristics of the crystal forms of the acid addition salts of the compounds represented by formula (I) or formula (Ia) described in the present invention.
It will be further appreciated that certain features of the invention, which are, for clarity, described in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the invention which are, for brevity, described in the context of a single embodiment, may also be provided separately or in any suitable subcombination.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. All patents and publications referred to herein are incorporated by reference in their entirety. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, the preferred methods, devices, and materials are described herein.
Definitions and general terms
The term "comprising" is open-ended, i.e. including what is specified in the invention, but not excluding other aspects.
The term "room temperature" as used herein means a temperature of from 10 ℃ to 40 ℃. In some embodiments, "room temperature" refers to a temperature from 20 ℃ to 30 ℃; in other embodiments, "room temperature" refers to a temperature from 25 ℃ to 30 ℃.
The term "pharmaceutically acceptable" as used herein refers to a substance that is acceptable from a toxicological point of view for pharmaceutical use and does not interact adversely with the active ingredient.
"XRPD" refers to X-ray powder diffraction.
Information such as change, crystallinity, crystal structure state and the like of the crystal form can be detected by X-ray powder diffraction (XRPD), and the method is a common means for identifying the crystal form. XRPD patterns refer to experimentally observed diffraction patterns or parameters derived therefrom. The powder X-ray diffraction pattern is characterized by the peak position (abscissa) and the peak intensity (ordinate). The peak position depends mainly on the structure of the crystalline form, is relatively insensitive to experimental details, while its relative peak intensity depends on many factors related to sample preparation and instrument geometry. Accordingly, in some embodiments, the crystalline form of the present invention is characterized by an XRPD pattern having certain peak positions, substantially as shown in the XRPD patterns provided in the figures herein. Also, the 2 θ measurement of the XRPD pattern may have experimental error, and the 2 θ measurement of the XRPD pattern may be slightly different from instrument to instrument and from sample to sample, so the 2 θ value cannot be considered absolute. According to the condition of an instrument used in the test, the diffraction peak has error tolerance of +/-0.1 degree, +/-0.2 degree, +/-0.3 degree, +/-0.4 degree or +/-0.5 degree; in some embodiments the diffraction peaks have a margin of error of ± 0.2 °.
The term "2 θ value" or "2 θ angle" refers to the position of the peaks in degrees of an experimental setup based on X-ray diffraction experiments and is the common abscissa unit of the diffraction pattern. The experimental setup required that if the reflection was diffracted when the incident beam formed an angle θ (θ) with a certain crystal, the reflected beam was recorded at an angle 2 θ (2 θ). It is to be understood that reference herein to specific 2 θ values for a particular polymorph is intended to refer to the 2 θ values (in degrees) measured using the X-ray diffraction experimental conditions described herein.
In the context of the present invention, the 2 θ values in the X-ray powder diffraction pattern are all in degrees (°).
"relative intensity" refers to the ratio of the intensity of the first strong peak to the intensity of the other peaks when the intensity of the first strong peak is 100% among all the diffraction peaks of an X-ray powder diffraction pattern (XRPD).
Differential Scanning Calorimetry (DSC) is to measure the temperature of a sample and an inert reference substance (usually alpha-Al) by continuously heating or cooling under the control of a program 2 O 3 ) The energy difference therebetween varies with temperature. The melting peak height of the DSC curve depends on many factors related to sample preparation and instrument geometry, while the peak position is relatively insensitive to experimental details. Thus, in some embodiments, the crystalline form of the present invention is characterized by a DSC profile with characteristic peak positions substantially as shown in the DSC profiles provided in the figures of the present invention. Meanwhile, the DSC profile may have experimental errors, and the peak position and peak value of the DSC profile may slightly differ from instrument to instrument and from sample to sample, so the peak position or peak value of the DSC endothermic peak cannot be regarded as absolute. Depending on the instrumentation used in this test, the melting peaks have a margin of error of + -1 deg.C, + -2 deg.C, + -3 deg.C, + -4 deg.C, or + -5 deg.C. In some embodiments the melting peak has a margin of error of ± 3 ℃. Differential Scanning Calorimetry (DSC) can also be used for detecting and analyzing whether the crystal form has crystal transformation or crystal mixing phenomenon.
Solids of the same chemical composition often form isomeric, or referred to as metamorphosis, isomers of different crystal structures under different thermodynamic conditions, and this phenomenon is called polymorphism or homomultiphase phenomenon. When the temperature and pressure conditions are changed, the variants are transformed into each other, and the phenomenon is called crystal transformation. Due to the crystal form transformation, the mechanical, electrical, magnetic and other properties of the crystal can be changed greatly. When the temperature of crystal form transformation is in a measurable range, the transformation process can be observed on a Differential Scanning Calorimetry (DSC) chart, and the DSC chart is characterized in that the DSC chart has an exothermic peak reflecting the transformation process and simultaneously has two or more endothermic peaks which are respectively characteristic endothermic peaks of different crystal forms before and after transformation.
By "antisolvent" is meant a fluid that facilitates precipitation of a product (or product precursor) from a solvent. The anti-solvent may comprise a cold gas, or a fluid that promotes precipitation by a chemical reaction, or a fluid that reduces the solubility of the product in the solvent; it may be the same liquid as the solvent but at a different temperature, or it may be a different liquid than the solvent.
"solvate" means having a solvent on the surface, in the crystal lattice, or on and in the crystal lattice which may be water, acetic acid, acetone, acetonitrile, benzene, chloroform, carbon tetrachloride, dichloro alkane, dimethyl sulfoxide, 1,4-dioxane, ethanol, ethyl acetate, butanol, t-butanol, N-dimethylacetamide, N-dimethylformamide, formamide, formic acid, heptane, hexane, isopropanol, methanol, methyl ethyl ketone, methyl pyrrolidone, mesitylene, nitromethane, polyethylene glycol, propanol, 2-acetone, pyridine, tetrahydrofuran, toluene, xylene, mixtures thereof, and the like. A specific example of a solvate is a hydrate, wherein the solvent on the surface, in the crystal lattice or on the surface and in the crystal lattice is water. The hydrates may or may not have other solvents than water on the surface of the substance, in the crystal lattice or both.
The term "equivalent" or its abbreviation "eq", as used herein, is the equivalent amount of the other raw materials required in terms of the equivalent relationship of the chemical reaction, based on the base material used in each step (1 equivalent).
Crystalline forms can be identified by a variety of techniques, such as X-ray powder diffraction (XRPD), infrared absorption spectroscopy (IR), melting point methods, differential Scanning Calorimetry (DSC), thermogravimetric analysis (TGA), nuclear magnetic resonance methods, raman spectroscopy, X-ray single crystal diffraction, dissolution calorimetry, scanning Electron Microscopy (SEM), quantitative analysis, solubility and dissolution rate, and the like.
The term "substantially as shown" means that at least 50%, or at least 60%, or at least 70%, or at least 80%, or at least 90%, or at least 95%, or at least 99% of the peaks in the X-ray powder diffraction pattern or DSC pattern or raman spectrum or infrared spectrum are shown in the figure.
When referring to a spectrogram or/and data appearing in a graph, "peak" refers to a feature that one skilled in the art would recognize as not being attributable to background noise.
In the context of the present invention, the word "about" or "approximately" when used or whether used, means within 10%, suitably within 5%, and especially within 1% of a given value or range. Alternatively, the term "about" or "approximately" means within an acceptable standard error of the mean for one of ordinary skill in the art. Whenever a number with a value of N is disclosed, any number within the values of N +/-1%, N +/-2%, N +/-3%, N +/-5%, N +/-7%, N +/-8% or N +/-10% is explicitly disclosed, wherein "+/-" means plus or minus.
The term "tautomer" or "tautomeric form" as used herein refers to structural isomers having different energies that can be interconverted by a low energy barrier (low energy barrier). If tautomerism is possible (e.g., in solution), then the chemical equilibrium of the tautomer can be reached. For example, proton tautomers (prototentauomers), also known as proton transfer tautomers (prototropic tautomers), include interconversions by proton migration, such as (4- ((S) -7- (((R) -6- (2-chloro-4-fluorophenyl) -5- (methoxycarbonyl) -2- (thiazol-2-yl) -3,6-dihydropyrimidin-4-yl) methyl) -3-oxohexahydroimidazo [1,5-a ] pyrazin-2 (3H) -yl) benzoic acid and (4- ((S) -7- (((R) -6- (2-chloro-4-fluorophenyl) -5- (methoxycarbonyl) -2- (thiazol-2-yl) -1,6-dihydropyrimidin-4-yl) methyl) -3-oxohexahydroimidazo [1,5-a ] pyrazin-2 (3H) -yl) benzoic acid tautomers (valtators) are interconverting into tautomeric forms unless otherwise indicated by the present invention.
The definition and convention of stereochemistry in the present invention is generally used with reference to the following documents: S.P. Parker, ed., mcGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, new York; and Eliel, E.and Wilen "S.," Stereochemistry of Organic Compounds ", john Wiley & Sons, inc., new York,1994. All stereoisomeric forms of the compounds of the present invention, including but in no way limited to, diastereomers, enantiomers, atropisomers, and mixtures thereof, such as racemic mixtures, form part of the present invention. Many organic compounds exist in optically active form, i.e., they have the ability to rotate the plane of plane polarized light. In describing optically active compounds, the prefix D, L or R, S is used to denote the absolute configuration of the chiral center of the molecule. The prefixes d, l or (+), (-) are used to designate the sign of the rotation of plane polarized light of the compound, with (-) or l indicating that the compound is left-handed and the prefix (+) or d indicating that the compound is right-handed. The chemical structures of these stereoisomers are identical, but their stereo structures are different. A particular stereoisomer may be an enantiomer, and a mixture of isomers is commonly referred to as a mixture of enantiomers. A mixture of enantiomers of 50.
The term "patient" as used herein refers to humans (including adults and children) or other animals. In some embodiments, "patient" refers to a human.
The term "treating" or "treatment" as used herein refers, in some embodiments, to ameliorating a disease or disorder (i.e., slowing or arresting or reducing the development of the disease or at least one clinical symptom thereof). In other embodiments, "treating" or "treatment" refers to mitigating or improving at least one physical parameter, including physical parameters that may not be perceived by the patient. In other embodiments, "treating" or "treatment" refers to modulating the disease or disorder, either physically (e.g., stabilizing a perceptible symptom) or physiologically (e.g., stabilizing a parameter of the body), or both. In other embodiments, "treating" or "treatment" refers to preventing or delaying the onset, occurrence, or worsening of a disease or disorder.
Pharmaceutical compositions of the salts of the invention
As described herein, comprise pharmaceutically acceptable excipients, such as any solvent, solid excipient, diluent, binder, disintegrant, or other liquid excipient, dispersant, flavoring or suspending agent, surfactant, isotonizing agent, thickening agent, emulsifier, preservative, solid binder, glidant or lubricant, etc., as used herein, as appropriate for the particular target dosage form. As described in the following documents: in Remington, the Science and Practice of Pharmacy,21st edition,2005, ed.D.B.Troy, lippincott Williams & Wilkins, philadelphia, and Encyclopedia of Pharmaceutical Technology, eds.J.Swarbrick and J.C.Boylan,1988-1999, marcel Dekker, new York, taken together with The disclosure of The literature, indicates that different excipients may be used In The formulation of pharmaceutically acceptable compositions and their well-known methods of preparation. Except insofar as any conventional adjuvant is incompatible with the compounds of the invention, e.g., any adverse biological effect produced or interaction in a deleterious manner with any other component of a pharmaceutically acceptable composition, their use is contemplated by the present invention.
Substances that may serve as pharmaceutically acceptable excipients include, but are not limited to, ion exchangers; aluminum; aluminum stearate; lecithin; serum proteins, such as human serum albumin; buffer substances such as phosphates; glycine; sorbic acid; potassium sorbate; partial glyceride mixtures of saturated vegetable fatty acids; water; salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts; colloidal silica; magnesium trisilicate; polyvinylpyrrolidone; polyacrylate esters; a wax; polyethylene-polyoxypropylene-blocking polymers; lanolin; sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; gum powder; malt; gelatin; talc powder; adjuvants such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols, such as propylene glycol and polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffering agents such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic salt; ringer's solution; ethanol; phosphoric acid buffer solution; and other non-toxic suitable lubricants such as sodium lauryl sulfate and magnesium stearate; a colorant; a release agent; coating materials; a sweetener; a flavoring agent; a fragrance; preservatives and antioxidants.
The crystal form of the acid addition salt or the pharmaceutical composition are suitable for treating acute and chronic viral infections of infectious hepatitis, especially for effectively inhibiting Hepatitis B Virus (HBV), and are suitable for treating or relieving diseases caused by viruses of patients, especially acute and chronic persistent HBV viral infections, chronic viral diseases caused by HBV can cause severe pathological changes, and chronic hepatitis B viral infections can cause cirrhosis and/or hepatocellular carcinoma in many cases.
Pharmaceutical compositions of the crystalline forms of the acid addition salts of the compounds of the present invention may be administered in any of the following ways: oral administration, inhalation by spray, topical administration, rectal administration, nasal administration, topical administration, vaginal administration, parenteral administration such as subcutaneous, intravenous, intramuscular, intraperitoneal, intrathecal, intraventricular, intrasternal, or intracranial injection or infusion, or by means of an explanted reservoir. Preferred modes of administration are oral, intramuscular, intraperitoneal or intravenous.
The crystalline forms of the acid addition salts of the compounds of the present invention or compositions containing them which are pharmaceutically acceptable may be administered in unit dosage form. The administration dosage form can be liquid dosage form or solid dosage form. The liquid dosage forms can be true solutions, colloids, microparticles, and suspensions. Other dosage forms such as tablet, capsule, dripping pill, aerosol, pill, powder, solution, suspension, emulsion, granule, suppository, lyophilized powder for injection, etc.
Oral tablets and capsules may contain excipients such as binding agents, for example syrup, acacia, sorbitol, tragacanth or polyvinylpyrrolidone; fillers, such as lactose, sucrose, corn starch, calcium phosphate, sorbitol, glycine; lubricants, such as magnesium stearate, talc, polyethylene glycol, silica; disintegrants, such as potato starch; or acceptable humectants such as sodium lauryl sulfate. The tablets may be coated by methods known in the art of pharmacy.
Oral liquids may be in the form of suspensions, solutions, emulsions, syrups or elixirs containing hydrated oils, or may be presented as a dry product for constitution with water or other suitable vehicle before use. Such liquid preparations may contain conventional additives such as suspending agents, sorbitol, cellulose methyl ether, glucose syrup, gelatin, hydroxyethyl cellulose, carboxymethyl cellulose, aluminium stearate gel, hydrogenated edible fats and oils, emulsifying agents, such as lecithin, sorbitan monooleate, acacia; or a non-aqueous carrier (which may comprise an edible oil), such as almond oil, an oil such as glycerol, ethylene glycol, or ethanol; preservatives, e.g. methyl or propyl p-hydroxybenzoate, sorbic acid. Flavoring or coloring agents may be added if desired.
Suppositories may contain conventional suppository bases such as cocoa butter or other glycerides.
For parenteral administration, the liquid dosage forms are generally prepared from the compound and a sterile vehicle. The carrier is preferably water. The compound can be dissolved in the carrier or made into suspension solution according to the concentration of the carrier and the drug, and the compound is firstly dissolved in water when made into the solution for injection, filtered and sterilized and then filled into a sealed bottle or ampoule.
When applied topically to the skin, the compounds of the present invention may be formulated in the form of a suitable ointment, lotion, or cream in which the active ingredient is suspended or dissolved in one or more carriers, which may be used in ointment formulations including, but not limited to: mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyethylene oxide, polypropylene oxide, emulsifying wax and water; lotions and creams may employ carriers including, but not limited to: mineral oil, sorbitan monostearate, tween 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water.
In general, it has proven advantageous, both in human medicine and in veterinary medicine, to administer the active compounds according to the invention in a total amount of from about 0.5 to 500mg, preferably from 1 to 100mg, per kg of body weight per 24 hours, if appropriate in multiple single doses, in order to achieve the desired effect. The amount of active compound contained in a single dose is preferably about 1 to 80mg, more preferably 1 to 50mg per kg body weight, but may be varied from the above-mentioned dose, i.e., depending on the kind and body weight of the subject to be treated, the nature and severity of the disease, the type of preparation and the mode of administration of the drug, and the period or interval of administration.
The pharmaceutical composition provided by the invention also comprises an anti-HBV medicament, wherein the anti-HBV medicament is an HBV polymerase inhibitor, an immunomodulator or interferon.
HBV drugs include lamivudine, telbivudine, tenofovir disoproxil, entecavir, adefovir dipivoxil, alfaferone, alloferon, west Mo Bai interleukin, clevudine, emtricitabine, fapronovir, interferon, poncin CP, intefen, interferon alpha-1 b, interferon alpha-2 a, interferon beta-1 a, interferon alpha-2, interleukin-2, mefenate, nitazoxanide, peginterferon alpha-2 a, ribavirin, robinsonine-A, sizopyran, euforavac, ritolimod, phosphazid, heplissav, interferon alpha-2 b, levamisole, propafegermanium, and the like.
The salt and the application of the pharmaceutical composition thereof
Another aspect of the invention is directed to a salt of a compound of the invention or a pharmaceutical composition for use in the preparation of a medicament for preventing, treating or ameliorating hepatitis b disease in a patient, comprising administering to the patient a pharmaceutically acceptable effective amount. Hepatitis B disease refers to liver disease caused by hepatitis B virus infection or hepatitis B infection, including acute hepatitis, chronic hepatitis, cirrhosis and hepatocellular carcinoma. Acute hepatitis b virus infection may be asymptomatic or manifest as acute hepatitis symptoms. Patients with chronic viral infections have active disease and can develop cirrhosis and liver cancer.
An "effective amount", "therapeutically effective amount" or "effective dose" of a salt and/or pharmaceutically acceptable pharmaceutical composition of the invention refers to an amount effective to treat or reduce the severity of one or more of the conditions mentioned herein. The salts or pharmaceutically acceptable pharmaceutical compositions of the present invention are effective over a fairly wide dosage range. For example, the daily dosage may be in the range of about 0.1mg to about 1000mg per person, divided into one or more administrations. The salts and pharmaceutical compositions according to the methods of the invention can be in any amount administered and by any route of administration effective to treat or reduce the severity of the disease. The exact amount necessary will vary depending on the condition of the patient, depending on age, general condition of the patient, severity of infection, particular factors, mode of administration, and the like. The salts or pharmaceutical compositions of the invention may be administered in combination with one or more other therapeutic agents, as discussed herein.
Drawings
Figure 1 is an X-ray powder diffraction (XRPD) pattern of form a of the hydrochloride salt;
FIG. 2 is a Differential Scanning Calorimetry (DSC) profile of the hydrochloride form A;
figure 3 is an X-ray powder diffraction (XRPD) pattern of form B of the hydrochloride salt;
figure 4 is a Differential Scanning Calorimetry (DSC) profile of form B of the hydrochloride salt;
figure 5 is an X-ray powder diffraction (XRPD) pattern of form a of the sulfate salt;
FIG. 6 is a Differential Scanning Calorimetry (DSC) profile of form A of the sulfate salt;
FIG. 7 is an X-ray powder diffraction (XRPD) pattern of hydrobromide form A;
figure 8 is a Differential Scanning Calorimetry (DSC) plot of hydrobromide form a;
figure 9 is an X-ray powder diffraction (XRPD) pattern of phosphate form a;
FIG. 10 is a Differential Scanning Calorimetry (DSC) profile of phosphate form A;
figure 11 is an X-ray powder diffraction (XRPD) pattern of mesylate salt form a;
FIG. 12 is a Differential Scanning Calorimetry (DSC) profile of mesylate form A;
figure 13 is an X-ray powder diffraction (XRPD) pattern of mesylate salt form B;
FIG. 14 is a Differential Scanning Calorimetry (DSC) profile of mesylate form B;
figure 15 is an X-ray powder diffraction (XRPD) pattern of phosphate form a after 10 days of storage under high humidity conditions;
fig. 16 is an X-ray powder diffraction (XRPD) pattern of comparative example 1.
General preparation and detection methods
The crystalline form may be prepared by a variety of methods including, but not limited to, for example, crystallization or recrystallization from a suitable solvent mixture; sublimation; solid state conversion from another phase; crystallization from a supercritical fluid; and spraying. Techniques for crystallization or recrystallization of crystalline forms of solvent mixtures include, but are not limited to, for example, solvent evaporation; reducing the temperature of the solvent mixture; seeding (crystal seeding) of a supersaturated solvent mixture of a compound and/or salt thereof; freeze drying the solvent mixture; and an anti-solvent (antisolvent) is added to the solvent mixture. Crystalline forms, including polymorphs, can be prepared using high throughput crystallization techniques.
Crystals (including polymorphs), methods of preparation, and characterization of drug crystals are discussed in Solid-State Chemistry of Drugs, S.R.Byrn, R.R.Pfeiffer, and J.G.Stowell, second edition, SSCI, west Lafayette, indiana (1999).
In crystallization techniques in which a solvent is utilized, the solvent is generally selected based on one or more factors including, but not limited to, for example, the solubility of the compound, the crystallization technique used, and the vapor pressure of the solvent. Combinations of solvents may be utilized. For example, the compound may be solubilized in a first solvent to obtain a solution, and then an anti-solvent is added to reduce the solubility of the compound in the solution and precipitate the crystal formation. An antisolvent is a solvent in which the compound has low solubility.
Seed crystals may be added to any crystallization mixture to promote crystallization. Seeding may be used to control the growth of a particular polymorph, and/or to control the grain size distribution of the crystallized product. Therefore, the calculation of the amount of seeds required depends on the size of the available seeds and the desired size of the average product particles, as described in "Programmed plating Batch Crystallizers", J.W.Mullin and J.Nyvlt, chemical Engineering Science,1971,26,369-377. Small sized seeds are generally required to effectively control crystal growth in the batch. Small size seeds can be produced by large crystals sieving, milling or micronization, or by solution microcrystallization. In crystal milling or micronization, care should be taken to avoid changing crystallinity from the desired crystalline form (i.e., to an amorphous form or other polymorphic form).
The cooled crystallization mixture can be filtered under vacuum and the isolated solid product washed with a suitable solvent (e.g., cold recrystallization solvent). After washing, the product can be dried under a nitrogen purge to give the desired crystalline form. The product may be analyzed by suitable spectroscopic or analytical techniques including, but not limited to, for example, differential Scanning Calorimetry (DSC), X-ray powder diffraction (XRPD), and thermogravimetric analysis (TGA) to ensure that a crystalline form of the compound has been formed. The resulting crystalline form may be produced in an isolated yield of greater than about 70% by weight, preferably greater than about 90% by weight, based on the weight of the compound initially used in the crystallization process. The product may optionally be de-agglomerated by co-grinding or by passing through a mesh screen.
The features and advantages of the present invention may be more readily understood by those of ordinary skill in the art after reading the following detailed description. It is to be understood that certain features of the invention, which are, for clarity reasons, described above and below in the context of separate embodiments, may also be combined to form a single embodiment. Conversely, various features of the invention which are, for brevity, described in the context of a single embodiment, may also be provided in combination to form a sub-combination thereof. The present disclosure is further illustrated by the following examples, which should not be construed as limiting the scope of the invention or to be limited to the specific steps described therein.
In the examples described below, all temperatures are given in degrees Celsius (. Degree. C.) unless otherwise indicated. Unless otherwise indicated, reagents were purchased from commercial suppliers such as Aldrich Chemical Company, arco Chemical Company and Alfa Chemical Company and used without further purification. General reagents were purchased from Shantou Wen Long chemical plant, guangdong Guanghua chemical plant, guangzhou chemical plant, shaoshou technology, qingdao Tenglong chemical reagent Co., ltd and Qingdao overseas chemical plant.
The NMR spectral data were measured by Bruker Avance 400 NMR spectrometer or Bruker Avance III HD 600 NMR spectrometer, CDC 13 ,DMSO-d6,CD 3 OD or d 6-propanone was used as solvent (reported in ppm) and TMS (0 ppm) or chloroform (7.26 ppm) was used as reference standard. When multiple peaks occur, the following abbreviations will be used: s (singlets), s,s (singlets, singlet), d (doublets), t (triplets ), m (multiplets, multiplets), br (broadpededwideams), dd (doublets of doublets), ddd (doublets of doublets, doublets), dt (doublets of triplets, doublets), 8978 zft 8978 (doublets of doublets, doublets), td (triplets of doublets, triplets), br. Coupling constant J, in Hertz (Hz).
The crystal form prepared by the invention is identified according to the following method:
(1) The X-ray powder diffraction (XRPD) analysis method used in the invention is as follows: empyrean diffractometer using (Cu, K alpha, K alpha 1) as radiation source
Figure RE-GDA0003680091810000131
：1.540598；Kα2
Figure RE-GDA0003680091810000132
:1.544426; k α 2/K α 1 intensity ratio: 0.50 Voltage was set at 45KV and current was set at 40mA. A powdery sample is prepared into a thin layer on a monocrystalline silicon sample holder, and is placed on a rotary sample table to be analyzed in 0.0168 DEG step length within the range of 3-40 deg. Data Collector software was used to collect Data, highScore Plus software processed the Data, and Data Viewer software read the Data.
(2) The Differential Scanning Calorimetry (DSC) analysis method used in the invention comprises the following steps: differential scanning calorimetry was performed using a TA Q2000 module with a thermoanalytical controller. Data were collected and analyzed using TAInstructions Thermal Solutions software. About 1-5mg of the sample was accurately weighed into a specially made aluminum crucible with a lid and the sample analysis was performed from room temperature to about 250 c using a 10 c/min linear heating device. During use, the DSC cell was purged with dry nitrogen at 50 mL/min. The endothermic peak was plotted downward, and the data was analyzed and displayed using a TAUniversal Analysis.
athers Xbridge-C18 (4.6X 150mm,5 μm). The detection wavelength was 250nm, the flow rate was 1.0mL/min, the column temperature was 35 ℃, and the mobile phase was acetonitrile-water (v/v = 40/60).
Low resolution Mass Spectral (MS) data were determined by Agilent 6320 series LC-MS spectrometer equipped with a G1312A binary pump and a G1316ATCC (column temperature maintained at 30 ℃), a G1329A autosampler and G1315B DAD detector applied for analysis, and an ESI source applied to the LC-MS spectrometer.
Both spectrometers were equipped with an Agilent Zorbax SB-C18 column, 2.1X 30mm,5 μm in size. The injection volume is determined by the sample concentration; the flow rate is 0.6mL/min; peaks of HPLC were recorded by UV-Vis wavelength at 210nm and 254 nm. The mobile phases were 0.1% formic acid in acetonitrile (phase a) and 0.1% formic acid in ultrapure water (phase B). Gradient elution conditions are shown in table 1:
table 1: gradient elution conditions for low resolution mass spectrometry mobile phase
Time (min) A(CH 3 CN,0.1％HCOOH) B(H 2 O,0.1％HCOOH)
0～3 5～100 95～0
3～6 100 0
6～6.1 100～5 0～95
6.1～8 5 95
The purity of the compounds was assessed by Agilent 1100 series High Performance Liquid Chromatography (HPLC) with UV detection at 210nm and 254nm on a Zorbax SB-C18 column, 2.1X 30mm,4 μm,10 minutes, flow rate 0.6mL/min,5-95% (0.1% formic acid in acetonitrile) in (0.1% formic acid in water), the column temperature was maintained at 40 ℃.
Chromatographic preparative separation of the Compounds was carried out by Agilent 1260 series High Performance Liquid Chromatography (HPLC) with UV detection at 278nm, calesil ODS-120 (4.6X 250mm,120A, 10u) column, flow rate of 1.0mL/min, mobile phase of (10 mM ZnSO) 4 +20mM L-valine buffer): methanol (v/v) =50/50, and the column temperature is maintained at 30 ℃.
The following acronyms are used throughout the invention:
Figure RE-GDA0003680091810000141
Detailed Description
The technical solutions in the embodiments of the present invention will be clearly and completely described below, but the embodiments of the present invention are not limited thereto.
Preparation of the Compound of formula (I)
Step 1) Synthesis of Compound 1-1
Figure RE-GDA0003680091810000142
Acetone (3138 kg) was charged into the reactor, 1,4-bis-Boc-2-piperazinecarboxylic acid (198.74 kg, 601.6 mol) was added with stirring, and after complete dissolution with stirring, (S) -1-phenylethylamine (80.0 kg, 660.2mol) was added. After the addition, the reaction is stirred for 18h at 30 plus or minus 5 ℃, the centrifugation is carried out, acetone (627.8 kg) is used for washing a filter cake, and the filter cake is dried for 16h in vacuum at 60 plus or minus 5 ℃ to obtain a white solid compoundProduct 1-1 (85.32kg, 31.4%). MS (ESI, pos.ion) m/z of 329.3[ m-H ]] - 。
Step 2) Synthesis of Compound 1-2
Figure RE-GDA0003680091810000151
Adding water (853.8 kg), ethyl acetate (923.0 kg) and a compound 1-1 (85.22 kg) into a reaction kettle in sequence, dropwise adding concentrated hydrochloric acid into the reaction mixture at 25 +/-5 ℃ while stirring to adjust the pH value to 3-4, and standing for layering. The aqueous layer was extracted with ethyl acetate (460.6 kg), the organic layers were combined, washed once with water (426.8 kg), and the solvent was evaporated under reduced pressure to give the crude product. Adding n-hexane (1472.8 kg) into the crude product for dilution, stirring at 25 +/-5 ℃ for 8h, and centrifuging to obtain a wet product of the compound 1-2. The wet product was dried under vacuum at 60. + -. 5 ℃ for 16h to give compound 1-2 as a white solid (60.33kg, 96.8%). MS (ESI, pos.ion) m/z of 329.2[ m-H ]] - 。
Step 3) Synthesis of Compounds 1-3
Figure RE-GDA0003680091810000152
DMF (442.4 kg) and Compound 1-2 (60.22kg, 182.3mol) were added to the reaction vessel. After the mixture is completely stirred and dissolved at 25 +/-5 ℃, N, N-diisopropylethylamine (47.0kg, 363.6 mol) and 2- (7-azabenzotriazole) N, N, N ', N' -tetramethylurea hexafluorophosphate (87.76kg, 230.8mol) are added, after stirring is carried out for 10min at a controlled temperature, dibenzylamine (43.4kg, 220.0mol) is added, stirring is carried out for 8h at a warm temperature, water (794.60 kg) is slowly added for dilution, stirring is continuously carried out for 2h at 25 +/-5 ℃, centrifugation and water washing (607.80 kg) is carried out, thus obtaining the crude compound 1-3. Transferring the crude product of the compound 1-3 into a reaction kettle, adding absolute ethyl alcohol (469.0 kg), heating and refluxing, cooling to 25 +/-5 ℃ after the solid is completely dissolved, keeping the temperature and stirring for 14h, centrifuging, washing the solid with ethanol (120.2 kg), and drying in vacuum at 60 +/-5 ℃ for 16h to obtain a white solid compound 1-3 (68.15kg, 73.3%). MS (ESI, pos.ion) m/z of 454.3[ m ] +H-56] + 。
Step 4) Synthesis of Compounds 1-4
Figure RE-GDA0003680091810000153
Tetrahydrofuran (551.0 kg), compound 1-3 (68.14kg, 133.7 mol) and sodium borohydride (15.07kg, 398.4 mol) are sequentially put into a reaction kettle, stirred and dissolved completely, then cooled to-15 +/-5 ℃ and slowly dropped with a prepared tetrahydrofuran solution of iodine (37.27 kg of iodine simple substance is dissolved by 244.0kg of tetrahydrofuran). After dripping, heating to 50 +/-2 ℃ for reaction for 24h, cooling to-15 +/-5 ℃, slowly dripping methanol (162 kg) for quenching reaction, continuing stirring for 2h after dripping is finished, and heating and refluxing until the solid is completely dissolved.
Removing the solvent by reduced pressure evaporation, adding ethyl acetate (1225.5 kg) and sodium hydroxide aqueous solution (45.65 kg of sodium hydroxide is dissolved in 454.4kg of water) into the residue, stirring and dissolving, layering, stirring and washing an organic layer by water (340.8 kg) for 30min, layering, removing the ethyl acetate by reduced pressure evaporation at 50 +/-5 ℃, adding ethanol (269.8 kg) into the residue for dilution, heating and refluxing, stirring until the solid is completely dissolved, cooling to 25 +/-5 ℃, stirring for 14h, centrifuging, washing the solid by ethanol (26.4 kg), and then drying the solid in vacuum at 60 +/-5 ℃ for 16h to obtain white solid compounds 1-4 (57.29kg, 86.4%). MS (ESI, pos.ion) m/z: 496.3[ 2 ], [ M + H ]] + 。
Step 5) Synthesis of Compounds 1-6
Figure RE-GDA0003680091810000161
Ethyl acetate (677.0 kg) and compound 1-4 (57.28kg, 115.6 mol) were added to the reactor in order, stirred uniformly, and then palladium on charcoal (5.79 kg) was added. Reacting the reaction mixture in a hydrogen atmosphere (about 1.0 MPa) at 50 ℃ for 12h, cooling to 25 +/-5 ℃, filtering, washing with ethyl acetate (258.0 kg), evaporating the filtrate under reduced pressure to remove the solvent, adding tetrahydrofuran (324.6 kg) into the obtained residue for diluting, stirring, adding sodium tert-butoxide (22.23kg, 231.3 mol), heating to reflux, reacting for 14h under the condition of heat preservation, cooling to 30 +/-5 ℃, adding water (18.23 kg) for quenching reaction. The reaction mixture was evaporated under reduced pressure to remove the solvent, and water (109.4 kg) was added to the residue, followed by stirring at 25. + -. 5 ℃ CCentrifuging for 1h, and washing with water (72.6 kg) to obtain crude compound 1-6. The crude compounds 1-6 were added with methyl tert-butyl ether (161.2 kg), stirred for 2h at 25 + -5 deg.C, centrifuged, and the solids were washed with methyl tert-butyl ether (26.8 kg) and then dried under vacuum at 60 + -5 deg.C for 16h to give compounds 1-6 as white solids (25.45kg, 91%). MS (ESI, pos.ion) m/z:483.3[2 ] M + H] + ； 1 H NMR(400MHz, CH 3 OH-d 4 )δ4.12(d,J＝10.6Hz,1H),4.04(d,J＝11.0Hz,1H),3.77–3.64(m,2H),3.55 (t,J＝8.9Hz,1H),3.08(dd,J＝9.3,5.2Hz,1H),2.87(td,J＝12.2,2.8Hz,1H),2.82–2.68 (m,2H),1.49(s,9H).
Step 6) Synthesis of Compounds 1-7
Figure RE-GDA0003680091810000162
N 2 A mixture of compounds 1-6 (26.76g, 110.9mmol), methyl 4-bromo-benzoate (26.23g, 121.99 mmol), palladium acetate (1.24g, 5.55mmol), tBu-XPhos (4.70g, 11.07mmol), cesium carbonate (54.19 g, 166.31 mmol) and 1,4-dioxane (400 mL) was reacted at 110 ℃ for 5h with protection, suction filtered over hot pad celite, and the filter cake was washed with dichloromethane (2680 mL). The filtrate was concentrated, and ethanol (168 mL) was added to the residue, followed by stirring at room temperature overnight. The filter cake was filtered with suction and washed successively with ethanol (168 mL) and water (2680 mL) to give a white solid (35.65g, 85.63%). MS (ESI, pos.ion) m/z 320.1[ m ] +H-56] + 。
Step 7) Synthesis of Compounds 1 to 8
Figure RE-GDA0003680091810000171
After compound 1-7 (48.17g, 128.31mmol), tetrahydrofuran (232 mL) and methanol (93 mL) were added to a dry reaction flask in this order, they were dissolved completely with stirring at room temperature, and a solution of lithium hydroxide monohydrate (16.15g, 384.93 mmol) in water (93 mL) was added. The reaction mixture was warmed to 50 ℃ and stirred for 40min, the heating was turned off and the temperature was reduced to room temperature. Water (232 mL) and petroleum ether (232 mL) were added to the reaction system, the layers were separated by extraction, the organic layer was discarded, and water was usedThe layer was extracted with petroleum ether (232 mL. Times.2). The aqueous phase was diluted with ice water (926 mL), the pH was adjusted to 3-4 with concentrated HCl while stirring, a large amount of solid precipitated, stirring at room temperature for about 2h, suction filtration, and vacuum drying of the filter cake to give 1-8 (43.97 g, 94.82%) as a white solid. MS (ESI, pos.ion) m/z 306.2[ M + H-56 ]] + 。
Step 8) Synthesis of Compounds 1-9
Figure RE-GDA0003680091810000172
After compounds 1 to 8 (43.97g, 121.67mmol) and methylene chloride (152 mL) were added to the dry flask in this order and stirred at room temperature, trifluoroacetic acid (152 mL) was added and stirred at room temperature for about 12 hours. The solvent was distilled off under reduced pressure, methylene chloride (152 mL) was added to the residue and the solvent was distilled off under reduced pressure twice. The residue was diluted with ethyl acetate (253 mL) and stirred at room temperature for about 3h to precipitate a large amount of solid. Filtration gave compounds 1-9 as white solids (43.05g, 94.28%). MS (ESI, pos.ion) m/z:262.1[ m ] +H] + 。
Step 9) Synthesis of Compound represented by formula (I)
Figure RE-GDA0003680091810000173
To a dry reaction flask were added in this order (R) -6- (bromomethyl) -4- (2-chloro-4-fluorophenyl) -2- (thiazol-2-yl) -1,4-dihydropyrimidine-5-carboxylic acid methyl ester (51.01g, 114.70mmol), compound 1-9 (43.05g, 114.70mmol), anhydrous potassium carbonate (31.71g, 229.4 mmol), and anhydrous ethanol (500 mL), the reaction mixture was reacted at 50 ℃ for 16h, filtered, the filter cake was washed with dichloromethane (510 mL) and anhydrous ethanol (510 mL) in this order, and the solvent was distilled off from the filtrate under reduced pressure. Adding water (510 mL) and ethyl acetate (510 mL) to the concentrated residue, diluting, separating layers, extracting the water layer with ethyl acetate (400 mL × 3), adding ethyl acetate (510 mL) to the water layer, adjusting pH to 6-7 with concentrated hydrochloric acid under stirring, precipitating a large amount of solid, filtering, dissolving the solid with dichloromethane (400 mL), washing the organic layer with water (200 mL × 3), and evaporating the solvent from the organic layer under reduced pressure to obtain a yellow solid represented by formula (I)The compound (56g, 78.1%) is shown. MS (ESI, pos.ion) m/z of 625.3[ m ] +H] + ； 1 H NMR(400MHz,CDCl 3 )δ9.62(s,1H),8.09(d,J＝8.8Hz,2H),7.87(d, J＝3.1Hz,1H),7.67(d,J＝8.9Hz,2H),7.49(d,J＝3.1Hz,1H),7.34–7.29(m,1H),7.16 (dd,J＝8.5,2.5Hz,1H),6.95(td,J＝8.4,2.4Hz,1H),6.23(s,1H),4.20–4.05(m,3H), 4.03–3.88(m,2H),3.62(s,3H),3.52–3.46(m,1H),3.38–3.25(m,1H),3.01–2.88(m, 2H),2.60–2.48(m,1H),2.35–2.22(m,1H).
Example 1
Example 1 is (4- ((S) -7- (((R) -6- (2-chloro-4-fluorophenyl) -5- (methoxycarbonyl) -2- (thiazol-2-yl) -1,6-dihydropyrimidin-4-yl) methyl) -3-oxohexahydroimidazo [1,5-a ] pyrazin-2 (3H) -yl) benzoate in crystalline form a, prepared as follows:
a compound represented by the formula (I) (0.3 g,0.5 mmol) and acetone (6 mL) are sequentially added into a dry reaction flask, the temperature is raised to 50 ℃, the solid is completely dissolved, concentrated hydrochloric acid (52mg, 37%) is diluted by water (0.15 mL) and then added into the reaction system, and after the addition is finished, the system is clarified, and then a large amount of solid is precipitated. Stirring for about 30min under heat preservation, turning off heating, and naturally cooling to room temperature. Stirring was continued for 66h at room temperature, filtered, washed with acetone (2 mL) and the solid dried under vacuum at 60 ℃ for 12h to give a yellow solid (0.3g, 90%).
And (4) result identification:
(1)LC-MS：MS(ESI,pos.ion)m/z:625.3[M+H] + 。
(2) Identified by Empyrean X-ray powder diffraction (XRPD) analysis: the obtained XRPD spectrum is shown in figure 1, the X-ray powder diffraction pattern of the hydrochloride form A comprises diffraction peaks with 2 theta angles of 8.78 degrees, 9.55 degrees, 10.07 degrees, 11.34 degrees, 11.99 degrees, 12.43 degrees, 12.84 degrees, 13.18 degrees, 13.59 degrees, 15.07 degrees, 15.40 degrees, 16.26 degrees, 17.04 degrees, 17.60 degrees, 17.96 degrees, 18.35 degrees, 19.18 degrees, 19.32 degrees, 20.09 degrees, 20.77 degrees, 21.77 degrees, 22.05 degrees, 22.77 degrees, 23.53 degrees, 23.78 degrees, 24.34 degrees, 24.99 degrees, 25.46 degrees, 25.65 degrees, 25.87 degrees, 26.13 degrees, 26.56 degrees, 26.98 degrees, 28.62 degrees, 29.10 degrees and 30.44 degrees, and the diffraction peak positions can have error tolerance of +/-0.2 degrees.
(3) Identified by TA Q2000 Differential Scanning Calorimetry (DSC) analysis: the scanning speed is 10 ℃/min, the obtained DSC curve is shown in figure 2, and the DSC curve comprises an endothermic peak of 211.0 ℃, and the error tolerance of +/-3 ℃ can be existed.
(4) Ion chromatography:
salt formation ratio of the compound of formula (Ia) in form a of (4- ((S) -7- (((R) -6- (2-chloro-4-fluorophenyl) -5- (methoxycarbonyl) -2- (thiazol-2-yl) -1,6-dihydropyrimidin-4-yl) methyl) -3-oxohexahydroimidazo [1,5-a ] pyrazin-2 (3H) -yl) benzoate to hydrochloric acid was determined by ion chromatography (TI-00375) with the process parameters as shown in the following table.
Figure RE-GDA0003680091810000181
Figure RE-GDA0003680091810000191
The test result shows that the salt forming molar ratio of the compound shown in the formula (Ia) in the crystal form A of the (4- ((S) -7- (((R) -6- (2-chloro-4-fluorophenyl) -5- (methoxycarbonyl) -2- (thiazole-2-yl) -1,6-dihydropyrimidin-4-yl) methyl) -3-oxohexahydroimidazo [1,5-a ] pyrazine-2 (3H) -yl) benzoate to hydrochloric acid is 1:1.
Example 2
Example 2 is (4- ((S) -7- (((R) -6- (2-chloro-4-fluorophenyl) -5- (methoxycarbonyl) -2- (thiazol-2-yl) -1,6-dihydropyrimidin-4-yl) methyl) -3-oxohexahydroimidazo [1,5-a ] pyrazin-2 (3H) -yl) benzoate crystalline form B, prepared as follows:
a compound represented by the formula (I) (0.3 g,0.5 mmol) and acetone (4.5 mL) were sequentially added to a dry reaction flask, the temperature was raised to 50 ℃ to completely dissolve the solid, concentrated hydrochloric acid (52mg, 37%) was diluted with water (0.45 mL) and added to the reaction system, and after the addition was completed, the system was clarified, and then a large amount of solid was precipitated. Stirring for about 30min under heat preservation, turning off heating, naturally cooling to room temperature, then continuing stirring for 17h at room temperature, filtering, washing filter cake with acetone (2 mL), and vacuum drying solid at 60 ℃ for 12h to obtain yellow solid (0.3g, 90%).
And (4) result identification:
(1)LC-MS：MS(ESI,pos.ion)m/z:625.3[M+H] + 。
(2) Identified by Empyrean X-ray powder diffraction (XRPD) analysis: the obtained XRPD spectrum is shown in figure 3, the X-ray powder diffraction pattern of the hydrochloride form B comprises diffraction peaks with 2 theta angles of 8.72 degrees, 11.95 degrees, 12.71 degrees, 13.05 degrees, 13.53 degrees, 14.50 degrees, 16.61 degrees, 17.21 degrees, 17.48 degrees, 17.81 degrees, 18.21 degrees, 18.93 degrees, 19.34 degrees, 19.92 degrees, 22.37 degrees, 22.57 degrees, 23.14 degrees, 23.48 degrees, 23.86 degrees, 24.16 degrees, 24.35 degrees, 24.74 degrees, 24.90 degrees, 25.47 degrees, 26.19 degrees, 26.99 degrees, 27.29 degrees, 28.24 degrees, 28.71 degrees and 35.27 degrees, and the diffraction peak positions can have error tolerance of +/-0.2 degrees.
(3) Identification by TA Q2000 Differential Scanning Calorimetry (DSC) analysis: the scan rate was 10 deg.C/min and the resulting DSC curve, as shown in FIG. 4, contained endothermic peaks at 183.2 deg.C and 214.0 deg.C, with a tolerance of error of + -3 deg.C.
(4) Ion chromatography:
the salt formation ratio of the compound shown in formula (Ia) in the (4- ((S) -7- (((R) -6- (2-chloro-4-fluorophenyl) -5- (methoxycarbonyl) -2- (thiazol-2-yl) -1,6-dihydropyrimidin-4-yl) methyl) -3-oxohexahydroimidazo [1,5-a ] pyrazine-2 (3H) -yl) benzoate form B to hydrochloric acid was determined by ion chromatography (TI-00375), with the process parameters referred to in example 1.
The test result shows that the salt forming molar ratio of the compound shown in the formula (Ia) in the crystal form B of the (4- ((S) -7- (((R) -6- (2-chloro-4-fluorophenyl) -5- (methoxycarbonyl) -2- (thiazole-2-yl) -1,6-dihydropyrimidin-4-yl) methyl) -3-oxohexahydroimidazo [1,5-a ] pyrazine-2 (3H) -yl) benzoate to hydrochloric acid is 1:1.
Example 3
Example 3 is (4- ((S) -7- (((R) -6- (2-chloro-4-fluorophenyl) -5- (methoxycarbonyl) -2- (thiazol-2-yl) -1,6-dihydropyrimidin-4-yl) methyl) -3-oxohexahydroimidazo [1,5-a ] pyrazin-2 (3H) -yl) benzoic acid sulfate crystalline form a, prepared as follows:
adding a compound (0.3 g,0.5 mmol) shown in the formula (I) and acetone (4.5 mL) into a dry reaction bottle in sequence, heating to 50 ℃, completely dissolving the solid, adding concentrated sulfuric acid (53mg, 98%) into water (0.3 mL), adding into the reaction system, separating out a large amount of solid after the addition is finished, keeping the temperature and stirring for about 30min, closing the heating, and naturally cooling to room temperature. Stirring was continued for 16h at room temperature, filtered, washed with acetone (2 mL) and the solid dried under vacuum at 60 ℃ for 12h to give a yellow solid (0.35g, 100%).
And (4) result identification:
(1)LC-MS：MS(ESI,pos.ion)m/z:625.3[M+H] + 。
(2) Identified by Empyrean X-ray powder diffraction (XRPD) analysis: the obtained XRPD spectrum is shown in figure 5, the X-ray powder diffraction pattern of the sulfate crystal form A comprises diffraction peaks with 2 theta angles of 5.94 degrees, 11.34 degrees, 12.45 degrees, 12.73 degrees, 13.66 degrees, 14.14 degrees, 15.15 degrees, 16.19 degrees, 16.82 degrees, 17.43 degrees, 17.70 degrees, 18.53 degrees, 19.23 degrees, 19.64 degrees, 20.63 degrees, 20.92 degrees, 21.63 degrees, 22.02 degrees, 22.24 degrees, 22.84 degrees, 23.80 degrees, 23.97 degrees, 24.70 degrees, 25.06 degrees, 25.37 degrees, 25.53 degrees, 26.02 degrees, 26.85 degrees, 28.03 degrees and 30.08 degrees, and the positions of the diffraction peaks can have error tolerance of +/-0.2 degrees.
(3) Identification by TA Q2000 Differential Scanning Calorimetry (DSC) analysis: the scanning speed was 10 ℃/min and the resulting DSC curve, as shown in figure 6, contained endothermic peaks at 156.0 ℃ and 213.3 ℃, with a margin of error of ± 3 ℃ being possible.
(4) Ion chromatography:
salt formation ratio of the compound of formula (Ia) in form a of (4- ((S) -7- (((R) -6- (2-chloro-4-fluorophenyl) -5- (methoxycarbonyl) -2- (thiazol-2-yl) -1,6-dihydropyrimidin-4-yl) methyl) -3-oxohexahydroimidazo [1,5-a ] pyrazin-2 (3H) -yl) benzoic acid sulfate salt form a to sulfuric acid was determined by ion chromatography (TI-00375) with reference to example 1 for the process parameters.
The test result shows that the salt formation molar ratio of the compound shown in the formula (Ia) in the crystal form A to sulfuric acid of (4- ((S) -7- (((R) -6- (2-chloro-4-fluorophenyl) -5- (methoxycarbonyl) -2- (thiazole-2-yl) -1,6-dihydropyrimidin-4-yl) methyl) -3-oxohexahydroimidazo [1,5-a ] pyrazine-2 (3H) -yl) benzoic acid sulfate is 1:1.
Example 4
Example 4 is (4- ((S) -7- (((R) -6- (2-chloro-4-fluorophenyl) -5- (methoxycarbonyl) -2- (thiazol-2-yl) -1,6-dihydropyrimidin-4-yl) methyl) -3-oxohexahydroimidazo [1,5-a ] pyrazin-2 (3H) -yl) benzoic acid hydrobromide crystalline form a, prepared as follows:
adding a compound (0.3 g,0.5 mmol) shown in the formula (I), acetone (4.5 mL) and water (0.45 mL) into a dry reaction bottle in sequence, stirring at room temperature until the solid is completely dissolved, heating to 50 ℃, diluting hydrobromic acid aqueous solution (0.11g, 40%) with acetone (0.5 mL), adding into the reaction system, after the addition is finished, the solution is turbid, gradually precipitating the solid, keeping the temperature and stirring for about 10min, closing and heating, naturally cooling to room temperature, then continuing stirring at room temperature for 9h, filtering, washing a filter cake with acetone (3 mL), and then performing vacuum drying at 60 ℃ for 12h to obtain a yellow solid (0.3 g, 90%).
And (4) result identification:
(1)LC-MS：(ESI,pos.ion)m/z:625.3[M+H] + 。
(2) Identified by Empyrean X-ray powder diffraction (XRPD) analysis: the obtained XRPD spectrum is shown in figure 7, the X-ray powder diffraction pattern of the hydrobromide crystal form A comprises diffraction peaks with 2 theta angles of 6.00 degrees, 6.80 degrees, 8.74 degrees, 9.56 degrees, 9.96 degrees, 12.06 degrees, 13.04 degrees, 15.12 degrees, 15.37 degrees, 16.26 degrees, 17.55 degrees, 18.03 degrees, 18.30 degrees, 19.15 degrees, 19.36 degrees, 19.98 degrees, 20.13 degrees, 20.64 degrees, 21.33 degrees, 21.91 degrees, 22.44 degrees, 22.61 degrees, 23.71 degrees, 24.19 degrees, 24.99 degrees, 25.21 degrees, 25.44 degrees, 26.19 degrees, 26.44 degrees, 26.85 degrees, 27.05 degrees, 27.66 degrees, 28.97 degrees and 30.47 degrees, and the diffraction peak positions can have error tolerance of +/-0.2 degrees.
(3) Identified by TA Q2000 Differential Scanning Calorimetry (DSC) analysis: the scan rate was 10 ℃/min and the resulting DSC curve, as shown in figure 8, contained an endothermic peak of 228.2 ℃, with a tolerance of ± 3 ℃ being possible.
(4) Ion chromatography:
salt formation ratio of the compound of formula (Ia) to hydrobromic acid in (4- ((S) -7- (((R) -6- (2-chloro-4-fluorophenyl) -5- (methoxycarbonyl) -2- (thiazol-2-yl) -1,6-dihydropyrimidin-4-yl) methyl) -3-oxohexahydroimidazo [1,5-a ] pyrazin-2 (3H) -yl) benzoic acid hydrobromide form a was determined by ion chromatography (TI-00375) with the process parameters referred to example 1.
The test result shows that the salt formation molar ratio of the compound shown in the formula (Ia) in the (4- ((S) -7- (((R) -6- (2-chloro-4-fluorophenyl) -5- (methoxycarbonyl) -2- (thiazole-2-yl) -1,6-dihydropyrimidin-4-yl) methyl) -3-oxohexahydroimidazo [1,5-a ] pyrazine-2 (3H) -yl) benzoic acid hydrobromide crystal form A to hydrobromic acid is 1:1.
Example 5
Example 5 is (4- ((S) -7- (((R) -6- (2-chloro-4-fluorophenyl) -5- (methoxycarbonyl) -2- (thiazol-2-yl) -1,6-dihydropyrimidin-4-yl) methyl) -3-oxohexahydroimidazo [1,5-a ] pyrazin-2 (3H) -yl) benzoic acid phosphate crystalline form a prepared as follows:
adding a compound (0.3 g,0.5 mmol) shown in the formula (I) and acetone (4.5 mL) into a dry reaction bottle in sequence, heating to 50 ℃, completely dissolving the solid, diluting phosphoric acid (0.12g, 85%) with water (0.15 mL), adding into a reaction system, clarifying the solution after adding, keeping the temperature, stirring for 30min, closing the heating, naturally cooling to room temperature, and gradually precipitating the solid. Stirring was continued for 22h at room temperature, filtered, and the filter cake was washed with acetone (2 mL) and then dried under vacuum at 60 ℃ for 12h to give a yellow solid (0.33g, 94%).
And (4) result identification:
(1)LC-MS：MS(ESI,pos.ion)m/z:625.3[M+H] + 。
(2) Identified by Empyrean X-ray powder diffraction (XRPD) analysis: the obtained XRPD spectrum is shown in figure 9, and the X-ray powder diffraction pattern of the phosphate crystal form A comprises diffraction peaks with 2 theta angles of 5.81 degrees, 6.46 degrees, 11.85 degrees, 12.85 degrees, 14.10 degrees, 15.53 degrees, 16.90 degrees, 17.35 degrees, 18.22 degrees, 19.32 degrees, 20.79 degrees, 23.20 degrees, 23.79 degrees, 24.80 degrees, 25.64 degrees, 27.33 degrees, 28.26 degrees, 28.97 degrees, 29.62 degrees and 30.38 degrees, and the positions of the diffraction peaks can have error tolerance of +/-0.2 degrees.
(3) Identification by TA Q2000 Differential Scanning Calorimetry (DSC) analysis: the scanning speed was 10 ℃/min, the obtained DSC curve is shown in figure 10, and comprises an endothermic peak at 207.2 ℃, and a margin of error of ± 3 ℃ can be present.
(4) Ion chromatography:
the salt formation ratio of the compound of formula (Ia) to phosphoric acid in form a of (4- ((S) -7- (((R) -6- (2-chloro-4-fluorophenyl) -5- (methoxycarbonyl) -2- (thiazol-2-yl) -1,6-dihydropyrimidin-4-yl) methyl) -3-oxohexahydroimidazo [1,5-a ] pyrazin-2 (3H) -yl) benzoic acid phosphate salt was determined by ion chromatography (TI-00586), with the process parameters referred to in example 1.
The test result shows that the salt formation molar ratio of the compound shown in the formula (Ia) in the (4- ((S) -7- (((R) -6- (2-chloro-4-fluorophenyl) -5- (methoxycarbonyl) -2- (thiazole-2-yl) -1,6-dihydropyrimidin-4-yl) methyl) -3-oxohexahydroimidazo [1,5-a ] pyrazine-2 (3H) -yl) benzoic acid phosphate crystal form A to phosphoric acid is 1:2.
Example 6
Example 6 is (4- ((S) -7- (((R) -6- (2-chloro-4-fluorophenyl) -5- (methoxycarbonyl) -2- (thiazol-2-yl) -1,6-dihydropyrimidin-4-yl) methyl) -3-oxohexahydroimidazo [1,5-a ] pyrazin-2 (3H) -yl) benzoic acid mesylate, form a, prepared as follows:
adding the compound (6 g,9.6 mmol) shown in the formula (I) and acetone (90 mL) into a dry reaction bottle in sequence, heating to 50 ℃ until the solid is completely dissolved, diluting methanesulfonic acid (1.01g, 10.56mmol) with water (1.8 mL), adding into a reaction system, keeping the temperature and stirring for 30min after the solid is completely dissolved, keeping the temperature and stirring for 30min, precipitating a large amount of solid in the process of keeping the temperature and stirring, closing the heating, and naturally cooling to room temperature. Stirring was continued at room temperature for 19h, filtered, washed with acetone (30 mL) and the solid dried under vacuum at 60 ℃ for 12h to give a yellow solid (5.73g, 82.8%).
And (4) result identification:
(1) LC-MS and Nuclear magnetic: MS (ESI, pos.ion) m/z:625.3[ 2 ], [ M + H ]]+； 1 H NMR(400MHz, CH 3 OH-d 4 )δ(ppm)8.06–8.01(m,3H),7.93(d,J＝3.1Hz,1H),7.73(d,J＝8.9Hz,2H), 7.56(dd,J＝8.7,6.0Hz,1H),7.30(dd,J＝8.6,2.5Hz,1H),7.14(td,J＝8.4,2.5Hz,1H), 6.21(s,1H),4.78(d,J＝16.1Hz,1H),4.60(d,J＝16.0Hz,1H),4.43–4.32(m,1H),4.26 (dd,J＝14.8,3.2Hz,1H),4.18(t,J＝9.4Hz,1H),3.90–3.73(m,3H),3.65(s,3H),3.62– 3.51(m,1H),3.39–3.35(m,1H),3.31–3.23(m,1H),2.70(s,3H).
(2) Identified by Empyrean X-ray powder diffraction (XRPD) analysis: the obtained XRPD spectrum is shown in fig. 11, and the X-ray powder diffraction pattern of the mesylate crystal form a comprises diffraction peaks with diffraction errors of 3.98 °, 7.91 °, 9.69 °, 10.21 °, 11.51 °, 11.86 °, 12.11 °, 13.38 °, 14.86 °, 15.21 °, 15.80 °, 16.82 °, 18.12 °, 18.38 °, 19.16 °, 19.62 °, 21.06 °, 21.66 °, 22.06 °, 22.57 °, 23.35 °, 23.81 °, 24.20 °, 24.90 °, 25.17 °, 26.35 °, 26.92 °, 28.42 °, 29.03 °, 29.89 °, 30.89 °, 4325 °, 31.90 °, 32.92 °, 3536, 35.78 °, 3926 °, 38.57 °, 39.59 °, 3528, 3835, 67, 43.42, 3524 °, 3524, 3534 °, 3975 ° and 3534 °.
(3) Identification by TA Q2000 Differential Scanning Calorimetry (DSC) analysis: the scan rate was 10 ℃/min and the resulting DSC curve is shown in figure 12, including an endothermic peak at 217.0 ℃, with a tolerance of ± 3 ℃ being possible.
Example 7
Example 7 is (4- ((S) -7- (((R) -6- (2-chloro-4-fluorophenyl) -5- (methoxycarbonyl) -2- (thiazol-2-yl) -1,6-dihydropyrimidin-4-yl) methyl) -3-oxohexahydroimidazo [1,5-a ] pyrazin-2 (3H) -yl) benzoic acid mesylate, crystalline form B, prepared as follows:
adding a compound (0.3 g,0.5 mmol) shown in the formula (I) and acetone (4.5 mL) into a dry reaction bottle in sequence, heating to 50 ℃, completely dissolving the solid, diluting methanesulfonic acid (51 mg) with water (0.3 mL), adding into a reaction system, clarifying the solution after adding, keeping the temperature, stirring for 30min, closing and heating, naturally cooling to room temperature, and gradually precipitating the solid. Stirring was continued for 12h at room temperature, filtered, washed with acetone (2 mL) and the solid dried under vacuum at 60 ℃ for 12h to give a yellow solid (0.25g, 70%).
And (4) result identification:
(1) LC-MS and Nuclear magnetic: MS (ESI, pos.ion) m/z of 625.3[ m ] +H] + 。 1 H NMR(400MHz, CH 3 OH-d 4 )δ(ppm)8.06–8.01(m,3H),7.93(d,J＝3.1Hz,1H),7.73(d,J＝8.9Hz,2H), 7.56(dd,J＝8.7,6.0Hz,1H),7.30(dd,J＝8.6,2.5Hz,1H),7.14(td,J＝8.4,2.5Hz,1H), 6.21(s,1H),4.78(d,J＝16.1Hz,1H),4.60(d,J＝16.0Hz,1H),4.43–4.32(m,1H),4.26 (dd,J＝14.8,3.2Hz,1H),4.18(t,J＝9.4Hz,1H),3.90–3.73(m,3H),3.65(s,3H),3.62– 3.51(m,1H),3.39–3.35(m,1H),3.31–3.23(m,1H),2.70(s,3H).
(2) Identified by Empyrean X-ray powder diffraction (XRPD) analysis: the obtained XRPD spectrum is shown in fig. 13, the X-ray powder diffraction pattern of mesylate form B includes diffraction peaks with 2 θ angles of 5.53 °, 6.69 °, 12.15 °, 12.46 °, 12.98 °, 14.34 °, 15.10 °, 16.35 °, 16.50 °, 17.59 °, 17.80 °, 18.41 °, 19.05 °, 19.43 °, 19.68 °, 20.04 °, 20.52 °, 20.79 °, 21.72 °, 22.29 °, 22.44 °, 22.83 °, 22.94 °, 23.74 °, 24.54 °, 25.52 °, 26.22 °, 27.66 °, 28.39 °, 28.74 °, 29.56 °, 30.46 °, and 31.03 °, and the diffraction peak positions may have an error tolerance of ± 0.2 °.
(3) Identification by TA Q2000 Differential Scanning Calorimetry (DSC) analysis: the scan rate was 10 deg.C/min and the resulting DSC curve, as shown in FIG. 14, contained 197.0 deg.C, and a margin of error of + -3 deg.C could be present.
Comparative example 1
Comparative example 1 was (4- ((S) -7- (((R) -6- (2-chloro-4-fluorophenyl) -5- (methoxycarbonyl) -2- (thiazol-2-yl) -3,6-dihydropyrimidin-4-yl) methyl) -3-oxohexahydroimidazo [1,5-a ] pyrazin-2 (3H) -yl) benzoic acid), a solid made according to the synthetic method of example 25 in PCT application WO2015132276, identified by Empyrean X-ray powder diffraction (XRPD) analysis: the resulting XRPD pattern is shown in figure 16.
Performance testing
1. Stability test
High-temperature test: placing a proper amount of the test product into a flat weighing bottle, spreading the test product into a thin layer with the thickness of less than or equal to 5mm, standing the test product at the temperature of 60 ℃ for 10 days, and sampling and detecting the appearance, related substances and purity on the 5 th day and the 10 th day. If the tested sample is changed obviously, the test is carried out at 40 ℃. If there is no significant change at 60 ℃, then the 40 ℃ test is not necessary.
High humidity test: taking a proper amount of a test article, placing the test article into a flat weighing bottle, spreading the test article into a thin layer with the thickness of less than or equal to 5mm, placing the test article for 10 days at the temperature of 25 ℃ and under the condition of relative humidity of 90 +/-5%, sampling and detecting appearance, related substances and purity on the 5 th day and the 10 th day, and simultaneously accurately weighing the weight of the test article before and after the test to examine the moisture absorption deliquescence performance of the test article. If the moisture absorption weight gain is more than 5%, performing the test by the same method under the conditions of 25 ℃ and 75% +/-5% of relative humidity; if the moisture absorption weight gain is less than 5 percent and other expedition items meet the requirements, the test is not carried out. ( Note: before the high-humidity test, the flat weighing bottle is put into a constant-humidity box (or a dryer containing a saturated potassium nitrate solution) for presaturation for one day, then the sample and the flat weighing bottle are weighed together, and the mass of the flat weighing bottle and the mass of the sample are recorded. )
And (3) illumination test: placing a proper amount of the test product into a flat weighing bottle, spreading into a thin layer with thickness of less than or equal to 5mm, placing in a light box (with ultraviolet) with an opening at the illumination of 4500 + -500 lx and the ultraviolet light of more than or equal to 0.7w/m 2 The sample was taken on days 5 and 10 to examine appearance, related substances and purity. The test results are shown in table 2 below:
in the tests of high temperature test, high humidity test and illumination test, whether the tested crystal form is subjected to crystal transformation or not is identified through Empyrean X-ray powder diffraction (XRPD) analysis.
Table 2: crystal form chemical stability influencing factor data of the salt of the invention
Figure RE-GDA0003680091810000231
Figure RE-GDA0003680091810000241
N/A represents not measured
And (4) conclusion: the crystal form of the salt of the present invention is stable under high temperature, high humidity and illumination conditions, wherein example 5 (phosphate crystal form a) is unstable under high temperature conditions, and after 10 days of high humidity, XRD detection occurs and thus, it is also unstable under high humidity conditions; of these, comparative example 1 is unstable under light conditions.
2. Pharmacokinetic evaluation of test animals following oral dosing of test samples
1. The experimental method comprises the following steps:
the beagle dogs were orally administered 5mg/kg of the test product in capsules, and blood was collected from the forelimb of the beagle dogs at different time points (0.083,0.25, 0.5,1,2,4,6,8, 10 and 24 hours) after administration, collected in an anticoagulant tube of EDTA-K2, and centrifuged to prepare plasma. Plasma samples were pre-treated and then quantitatively analyzed by multiplex reaction ion monitoring (MRM) on a triple quadrupole tandem mass spectrometer. Pharmacokinetic parameters were calculated using a non-compartmental model using WinNonlin 6.1 software.
Table 3: in vivo metabolism test data of beagle dog for samples of examples and comparative examples
Figure RE-GDA0003680091810000242
The experimental results show that the exposure of example 1 (hydrochloride crystal form a), example 2 (hydrochloride crystal form B), example 3 (sulfate crystal form a), example 4 (hydrobromide crystal form a), example 5 (phosphate crystal form a) and example 6 (methanesulfonate crystal form a) in beagle dogs is better, and is obviously better than the exposure of example 7 methanesulfonate crystal form B and comparative example 1 in beagle dogs, which shows that the compounds have good absorption in beagle dogs and good application prospects in anti-HBV virus aspect.
It should be understood that the above-described embodiments of the present invention are merely examples for clearly illustrating the present invention, and are not intended to limit the embodiments of the present invention. Other variations and modifications will be apparent to persons skilled in the art in light of the above description. This need not be, nor should it be exhaustive of all embodiments. Any modification, equivalent replacement, and improvement made within the spirit and principle of the present invention should be included in the protection scope of the claims of the present invention.

Claims (9)

1. An acid addition salt of a compound shown as formula (I) or formula (Ia), wherein the acid addition salt comprises hydrochloride crystal form A, hydrochloride crystal form B, sulfate crystal form A and hydrobromide crystal form A;
Figure FDA0003876152460000011
the X-ray powder diffraction pattern of the hydrochloride crystal form A comprises diffraction peaks with 2 theta angles of 10.07 +/-0.2 degrees, 11.34 +/-0.2 degrees, 11.99 +/-0.2 degrees, 12.84 +/-0.2 degrees, 13.18 +/-0.2 degrees, 16.26 +/-0.2 degrees, 17.60 +/-0.2 degrees, 18.35 +/-0.2 degrees, 19.18 +/-0.2 degrees, 20.09 +/-0.2 degrees and 20.77 +/-0.2 degrees;
the X-ray powder diffraction pattern of the hydrochloride crystal form B comprises diffraction peaks with 2 theta angles of 11.95 +/-0.2 degrees, 13.05 +/-0.2 degrees, 13.53 +/-0.2 degrees, 14.50 +/-0.2 degrees, 16.61 +/-0.2 degrees, 18.21 +/-0.2 degrees, 18.93 +/-0.2 degrees, 19.92 +/-0.2 degrees, 22.37 +/-0.2 degrees and 23.14 +/-0.2 degrees;
the X-ray powder diffraction pattern of the sulfate crystal form A comprises diffraction peaks with 2 theta angles of 5.94 +/-0.2 degrees, 11.34 +/-0.2 degrees, 12.73 +/-0.2 degrees, 14.14 +/-0.2 degrees, 15.15 +/-0.2 degrees, 16.82 +/-0.2 degrees, 17.43 +/-0.2 degrees, 18.53 +/-0.2 degrees, 19.23 +/-0.2 degrees and 22.02 +/-0.2 degrees;
the X-ray powder diffraction pattern of the hydrobromide crystal form A comprises diffraction peaks with 2 theta angles of 6.00 +/-0.2 degrees, 6.80 +/-0.2 degrees, 9.56 +/-0.2 degrees, 12.06 +/-0.2 degrees, 13.04 +/-0.2 degrees, 16.26 +/-0.2 degrees, 18.30 +/-0.2 degrees, 19.15 +/-0.2 degrees, 19.98 +/-0.2 degrees and 22.61 +/-0.2 degrees.
2. The acid addition salt of claim 1, characterized in that the X-ray powder diffraction pattern of form a of the hydrochloride salt comprises ± 0.2 °, 9.55 ± 0.2 °, 10.07 ± 0.2 °, 11.34 ± 0.2 °, 11.99 ± 0.2 °, 12.43 ± 0.2 °, 12.84 ± 0.2 °, 13.18 ± 0.2 °, 13.59 ± 0.2 °, 15.07 ± 0.2 °, 15.40 ± 0.2 °, 16.26 ± 0.2 °, 17.04 ± 0.2 °, 17.60 ± 0.2 °, 17.96 ± 0.2 °, 18.35 ± 0.2 °, 19.18 ± 0.2 °, 19.32 ± 0.2 °, 20.09 ± 0.2 °, 20.77 ± 0.2 °, 3238 ± 320.2 °, 22.05 ± 0.2 °, 22.77 ± 0.2.2.53 ± 0.2 °, 3238 ± 0.26 °, 320.26 ± 0.26 °,2 °, 2.26 ± 0.26 ± 0.28 ± 0.26 °, 3228 ± 0.26 °,2 ° 2.25 ± 0.26 °,2 ° 2.26 ± 0.25 ± 0.26 °;
or the X-ray powder diffraction pattern of the hydrochloride crystal form B comprises diffraction peaks of + -0.2 degrees of 2 theta, + -0.2 degrees of 11.95 + -0.2 degrees of 12.71 + -0.2 degrees of 13.05 + -0.2 degrees of 13.53 + -0.2 degrees of 14.50 + -0.2 degrees of 16.61 + -0.2 degrees of 17.21 + -0.2 degrees of 17.48 + -0.2 degrees of 17.81 + -0.2 degrees of 18.21 + -0.2 degrees of 18.93 + -0.2 degrees of 19.34 + -0.2 degrees of 19.92 + -0.2 degrees of 3238 + -32x3238 + -0.2 degrees of 22.57 + -0.2 degrees of 23.14 + -0.2 degrees of 23.48 + -0.2 degrees of 23.86 + -0.2 degrees of 24.16 + -0.2 degrees of 24.35 + -0.2 degrees of 24.74 + -0.2 degrees of 24.90 + -0.2 degrees of 25.47 + -0.26.26.19.19.19 + -0.2 degrees of 3228 degrees of 320.28 DEG + -2 DEG;
or the X-ray powder diffraction pattern of the sulfate crystal form A comprises diffraction peaks of + -0.2 degrees of 2 theta angles of + -0.2 degrees of 11.34 + -0.2 degrees of 12.45 + -0.2 degrees of 12.73 + -0.2 degrees of 13.66 + -0.2 degrees of 14.14 + -0.2 degrees of 15.15 + -0.2 degrees of 16.19 + -0.2 degrees of 16.82 + -0.2 degrees of 17.43 + -0.2 degrees of 17.70 + -0.2 degrees of 18.53 + -0.2 degrees of 19.23 + -0.2 degrees of 19.64 + -0.2 degrees of 20.63 + -0.2 degrees of 20.92 + -0.2 degrees of 21.63 + -0.2 degrees of 22.02 + -0.2 degrees of 22.24 + -0.2 degrees of 22.84 + -0.2 degrees of 23.80 + -0.2 degrees of 23.97 + -0.2 degrees of 24.70 + -0.06 + -0.2 degrees of 22.2 degrees of 22.25.2 degrees of 37.25.25.37.37.2 degrees of 3727.62 degrees of 3728 + -0.2 degrees of 3728 DEG + -0.2 degrees of 3727 DEG + -0.2 degrees of 3728 DEG + -0.2 degrees of X-2 degrees of 3723 DEG + -0;
or the X-ray powder diffraction pattern of the hydrobromide crystal form A comprises 2 theta angles of 6.00 +/-0.2 degrees, 6.80 +/-0.2 degrees, 8.74 +/-0.2 degrees, 9.56 +/-0.2 degrees, 9.96 +/-0.2 degrees, 12.06 +/-0.2 degrees, 13.04 +/-0.2 degrees, 15.12 +/-0.2 degrees, 15.37 +/-0.2 degrees, 16.26 +/-0.2 degrees, 17.55 +/-0.2 degrees, 18.03 +/-0.2 degrees, 18.30 +/-0.2 degrees, 19.15 +/-0.2 degrees, 19.36 +/-0.2 degrees, 19.98 +/-0.2 degrees diffraction peaks of 20.13 + -0.2 °, 20.64 + -0.2 °, 21.33 + -0.2 °, 21.91 + -0.2 °, 22.44 + -0.2 °, 22.61 + -0.2 °, 23.71 + -0.2 °, 24.19 + -0.2 °, 24.99 + -0.2 °, 25.21 + -0.2 °, 25.44 + -0.2 °, 26.19 + -0.2 °, 26.44 + -0.2 °, 26.85 + -0.2 °, 27.05 + -0.2 °, 27.66 + -0.2 °, 28.97 + -0.2 ° and 30.47 + -0.2 °.
3. The acid addition salt according to claim 2, wherein the hydrochloride form a has an X-ray powder diffraction pattern substantially as shown in figure 1;
or said hydrochloride form B has an X-ray powder diffraction pattern substantially as shown in figure 3;
or said sulfate form a has an X-ray powder diffraction pattern substantially as shown in figure 5;
or the hydrobromide form A has an X-ray powder diffraction pattern substantially as shown in figure 7.
4. The acid addition salt of claim 1, wherein the differential scanning calorimetry trace of form a of the hydrochloride salt comprises an endothermic peak at 211.0 ℃ ± 3 ℃;
or a differential scanning calorimetry trace of form B of the hydrochloride salt comprising endothermic peaks at 183.2 ℃ ± 3 ℃ and 214.0 ℃ ± 3 ℃;
or a differential scanning calorimetry trace of said sulfate form A comprises endothermic peaks at 156.0 ℃ ± 3 ℃ and 213.3 ℃ ± 3 ℃;
or a differential scanning calorimetry trace of said hydrobromide form A comprising an endothermic peak at 228.2 ℃ ± 3 ℃.
5. The acid addition salt of claim 4, wherein the hydrochloride form A has a differential scanning calorimetry trace substantially as shown in figure 2;
or said hydrochloride form B has a differential scanning calorimetry trace substantially as shown in figure 4;
or said sulfate form a has a differential scanning calorimetry pattern substantially as shown in figure 6;
or the hydrobromide form A has a differential scanning calorimetry pattern substantially as shown in figure 8.
6. A pharmaceutical composition comprising an acid addition salt according to any one of claims 1 to 5, and a pharmaceutically acceptable excipient therefor.
7. Use of an acid addition salt according to any one of claims 1 to 5 or a pharmaceutical composition according to claim 6 for the preparation of a medicament for the prevention, treatment or alleviation of a viral disease in a patient.
8. The use of claim 7, wherein the viral disease comprises hepatitis B infection or a disease caused by hepatitis B infection.
9. The use of claim 8, wherein the disease caused by hepatitis B infection comprises cirrhosis or hepatocellular carcinoma.
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